Differential mast cell phenotypes in benign versus cancer tissues and prostate cancer oncologic outcomes. Issue 4 (26th January 2021)

• Record Type: Journal Article
• Authors: Hempel Sullivan, Heidi; Maynard, Janielle P; Heaphy, Christopher M; Lu, Jiayun; De Marzo, Angelo M; Lotan, Tamara L; Joshu, Corinne E; Sfanos, Karen S
• Is Part Of: Journal of pathology. Volume 253:Issue 4(2021)
• Page Start: 415
• Page End: 426
• Publication Date: 2021-01-26
• Subjects: prostate cancer -- mast cells -- metastases -- CXCR4 -- TFE3 -- KIT -- microenvironment; Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.5606
• Languages: English
• ISSNs: 0022-3417

Abstract

Abstract: We reported previously that high numbers of mast cells in benign (extra‐tumoral) regions of the prostate are associated with worse outcomes after radical prostatectomy including biochemical recurrence and the development of metastases. Herein, with a cohort of 384 men, we performed mast cell subtyping and report that higher minimum number of the tryptase‐only (MCT ) subset of extra‐tumoral mast cells is associated with increased risk of biochemical recurrence (comparing highest to lowest tertiles: HR 2.32, 95% CI 1.37–3.93; P ‐trend = 0.002), metastases (HR 3.62, 95% CI 1.75–7.47; P ‐trend 0.001), and death from prostate cancer (HR 2.87, 95% CI 1.19–6.95; P ‐trend = 0.02). Preliminary RNA sequencing and comparison of benign versus cancer tissue mast cells revealed differential expression of additional site‐specific genes. We further demonstrate that the genes CXCR4 and TFE3 are more highly expressed in tumor‐infiltrating mast cells as well as other tumor‐infiltrating immune cells and in tumor cells, respectively, and represent an altered tumor microenvironment. KIT variants were also differentially expressed in benign versus cancer tissue mast cells, with KIT variant 1 (GNNK + ) mast cells identified as more prevalent in extra‐tumoral regions of the prostate. Finally, using an established mouse model, we found that mast cells do not infiltrate Hi‐Myc tumors, providing a model to specifically examine the role of extra‐tumoral mast cells in tumorigenesis. Hi‐Myc mice crossed to mast cell knockout (Wsh) mice and aged to 1 year revealed a higher degree of pre‐invasive lesions and invasive cancer in wild‐type mice versus heterozygous and knockout mice. This suggests a dosage effect where higher numbers of extra‐tumoral mast cells resulted in higher cancer invasion. Overall, our studies provide further evidence for a role of extra‐tumoral mast cells in driving adverse prostate cancer outcomes. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.